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Clinical Case Reports Oct 2021There are various causes of childhood poikiloderma. A proper history and clinical examination may help to get conclusion and narrow down the differentials for the causes...
There are various causes of childhood poikiloderma. A proper history and clinical examination may help to get conclusion and narrow down the differentials for the causes of poikiloderma.
PubMed: 34703608
DOI: 10.1002/ccr3.4977 -
Skin Health and Disease Mar 2021Rare syndromic skin disorders may represent a diagnostic challenge.
BACKGROUND
Rare syndromic skin disorders may represent a diagnostic challenge.
AIMS
We report a unique case associating cutaneous manifestations and developmental delay.
MATERIALS & METHODS
The affected 14 months old boy had poikiloderma, facial dysmorphism with deep-set eyes, atrichia, as well as nail dysplasia and non-descended testes. In addition, his psychomotor development was delayed. Exome sequencing and molecular karyotyping via array-CGH (oligo-array, 180k Agilent, design 22060) were performed.
RESULTS
Mutations in RECQL4 (found in patients with RTS2) were first excluded. In the ANAPC1 gene, a novel combination of a recurrent intronic mutation (c.2705-198C>T) and a deletion of the second ANAPC1 allele was detected, thus confirming the clinical diagnosis of RTS1. The deletion on chromosome 2q13 comprised further genes and spanned 1,7 megabases. Heterozygous deletions in this region are known as 2q13 microdeletion syndrome and are associated with developmental delay, autism and facial dysmorphism.
DISCUSSION
The genetic findings most probably explain both, the RTS1 features and the developmental delay. Genetic diagnosis in RTS is indispensable to confirm the specific subtype and its associated risks: juvenile cataracts are features of RTS1 (ANAPC1 gene), whereas a high risk of osteosarcoma is part of RTS2 (RECQL4 gene). Thus, the patient described here is at high risk for the development of juvenile cataracts and requires regular ophthalmologic examination.
CONCLUSION
This case report underlines the necessity of thorough clinical diagnosis prior to genetic diagnosis of RTS1, since the recurrent intronic ANAPC1 mutation is otherwise missed.
PubMed: 35664819
DOI: 10.1002/ski2.12 -
PloS One 2013Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line...
Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.
Topics: Blister; Blotting, Western; Cell Adhesion; Cell Line; Cell Movement; Cell Proliferation; Epidermis; Epidermolysis Bullosa; Flow Cytometry; Focal Adhesions; Humans; Immunoprecipitation; Integrin beta1; Integrins; Keratinocytes; Membrane Proteins; Neoplasm Proteins; Periodontal Diseases; Photosensitivity Disorders; Protein Binding
PubMed: 23776470
DOI: 10.1371/journal.pone.0065341 -
Experimental and Therapeutic Medicine Nov 2020Kindler syndrome (KS) is a rare subtype of epidermolysis bullosa that is inherited in an autosomal recessive manner with mutations in . A number of mutations in have...
Kindler syndrome (KS) is a rare subtype of epidermolysis bullosa that is inherited in an autosomal recessive manner with mutations in . A number of mutations in have been identified in KS. The current study reported a 33-year-old Chinese man who exhibited a wide variety of clinical features, including formation of blisters, photosensitivity, cutaneous atrophy and poikiloderma, telangiectasia of the face and neck, contracture of the end limbs, nail dystrophy, muscle, eye and oral damage, tympanitis, esophagus narrowing, pneumothorax and palmoplantar keratoderma. The patient's parents were healthy and the patient had no siblings or children. Peripheral blood was obtained from the patient, his parents and 100 controls, who were admitted to the Dermatology Clinic of Shanghai Skin Disease Hospital, Shanghai, China. A multi-gene panel test consisting of 541 genetic loci of monogenic hereditary diseases was performed. The results identified one novel homogenous mutation in the patient: c.1885_1901del (p.Val629fs) on exon 15 in . The patient's parents exhibited heterogeneous identical mutations. This mutation was absent in the control group. The results of the multi-gene panel test were further verified by Sanger sequencing. Based on the clinical manifestations and genetic analysis, KS was diagnosed in the patient. The current study reported a Chinese case of KS with one novel mutation c.1885_1901del in and presented a brief summary of all pathogenic mutations in that have been reported in KS between 1984 and May 2020 via a PubMed literature search.
PubMed: 32973952
DOI: 10.3892/etm.2020.9233 -
Journal of Pediatric Genetics Mar 2023Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood,...
Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.
PubMed: 36684545
DOI: 10.1055/s-0040-1721077 -
FEBS Letters Aug 2015Mpn1 is an exoribonuclease that modifies the spliceosomal small nuclear RNA (snRNA) U6 by trimming its oligouridine tail and introducing a cyclic phosphate group (>p)....
Mpn1 is an exoribonuclease that modifies the spliceosomal small nuclear RNA (snRNA) U6 by trimming its oligouridine tail and introducing a cyclic phosphate group (>p). Mpn1 deficiency induces U6 3' end misprocessing, accelerated U6 decay and pre-mRNA splicing defects. Mutations in the human MPN1 gene are associated with the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Here we present the deep sequencing of the >p-containing transcriptomes of mpn1Δ fission yeast and PN cells. While in yeast U6 seems to be the only substrate of Mpn1, human Mpn1 also processes U6atac snRNA. PN cells bear unstable U6atac species with aberrantly long and oligoadenylated 3' ends. Our data corroborate the link between Mpn1 and snRNA stability suggesting that PN could derive from pre-mRNA splicing aberrations.
Topics: Base Sequence; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Molecular Sequence Data; Neutropenia; Phosphoric Diester Hydrolases; RNA Processing, Post-Transcriptional; RNA Splicing; RNA Stability; RNA, Small Nuclear; Sequence Analysis, RNA; Skin Abnormalities
PubMed: 26213367
DOI: 10.1016/j.febslet.2015.06.046 -
Human Molecular Genetics Nov 2010Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone...
Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone marrow failure, cancer predisposition and other features. Approximately 50% of DC patients remain genetically uncharacterized. All the DC genes identified to date are important in telomere maintenance. To determine the genetic basis of the remaining cases of DC, we undertook linkage analysis in 20 families and identified a common candidate gene region on chromosome 16 in a subset of these. This region included the C16orf57 gene recently identified to be mutated in poikiloderma with neutropenia (PN), an inherited poikiloderma displaying significant clinical overlap with DC. Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families. In addition, three of six families previously classified as Rothmund-Thomson syndrome (RTS-a poikiloderma that is sometimes confused with PN) were also found to have homozygous C16orf57 mutations. Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls. These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. This study also highlights the multi-system nature (wider than just poikiloderma and neutropenia) of the clinical features of affected individuals (and therefore house-keeping function of C16orf57), a possible role for C16orf57 in apoptosis, as well as a distinct difference from previously characterized DC patients because telomere length was normal.
Topics: Case-Control Studies; Consanguinity; DNA Mutational Analysis; Dyskeratosis Congenita; Female; GTPase-Activating Proteins; Genetic Linkage; Homozygote; Humans; Male; Mutation; Neutropenia; Nuclear Proteins; Pigmentation Disorders; Polymorphism, Single Nucleotide; Rothmund-Thomson Syndrome; Telomere
PubMed: 20817924
DOI: 10.1093/hmg/ddq371 -
Orphanet Journal of Rare Diseases Dec 2014Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In...
BACKGROUND
Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease.
METHODS
Patient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy.
RESULTS
Patient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state.
CONCLUSIONS
This is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.
Topics: Adolescent; Aged, 80 and over; Blister; Cells, Cultured; Child; Child, Preschool; Epidermolysis Bullosa; Female; Humans; Keratinocytes; Male; Middle Aged; Mitochondria; Oxidative Stress; Periodontal Diseases; Photosensitivity Disorders
PubMed: 25528446
DOI: 10.1186/s13023-014-0211-8 -
The Tohoku Journal of Experimental... Apr 2022Myositis-specific autoantibodies are relevant factors that define the disease phenotype of dermatomyositis (DM). Anti-Mi-2 antibody-positive DM patients may present with...
Myositis-specific autoantibodies are relevant factors that define the disease phenotype of dermatomyositis (DM). Anti-Mi-2 antibody-positive DM patients may present with the typical skin lesions and prominent myositis. On the other hand, adult DM patients with anti-TIF-γ antibody seem to be associated with internal malignancy. Here, we report a rare case of juvenile dermatomyositis (JDM) exhibiting anti-Mi-2 and anti-transcriptional intermediary factor-1 gamma (TIF1-γ) antibodies, with no internal malignancy. A 16-year-old female Japanese patient under treatment with a 2-year history of chronic eczematous lesions was admitted to our department with elevated levels of muscle enzymes. Characteristic skin changes, such as Gottron's papules of the hand, heliotrope rash of the eyelids, and poikiloderma-like legions and diffuse pigmentation on the back, were observed. Histologically, the patient's skin was characterized by the presence of lymphocytic vascular inflammation and endothelial swelling, which are consistent with DM. Severe symmetric proximal muscle weakness, elevated serum muscle enzymes and the presence of anti-TIF1-γ and Mi-2 antibodies were noted. The diagnosis of JDM was made according to the European League Against Rheumatism (EULAR) diagnostic criteria. A high dose of corticosteroids and following intravenous cyclophosphamide treatment (750 mg three times) resulted in an improvement in clinical manifestations and functional outcomes, and recurrence did not occur. Estimation of autoantibodies may serve as an ancillary tool in delineating and defining distinct clinical phenotypes in JDM.
Topics: Autoantibodies; Dermatomyositis; Eczema; Female; Humans; Myositis; Neoplasms
PubMed: 35296571
DOI: 10.1620/tjem.2022.J006 -
Blood Science (Baltimore, Md.) Apr 2023Rothmund-Thomson syndrome (RTS) is a rare autosomal-recessive disorder with clinical features consisting of rash, poikiloderma, sparse hair, short stature, juvenile...
Rothmund-Thomson syndrome (RTS) is a rare autosomal-recessive disorder with clinical features consisting of rash, poikiloderma, sparse hair, short stature, juvenile cataracts, skeletal abnormalities, and cancer predisposition. Genetic studies involving detection of pathogenic variants provide the diagnostic certitude. Osteosarcoma was found in two-thirds -mutated RTS patients, while hematological malignancies were rarely reported. The variant diversity of gene has not been fully identified and mutations associated with hematologic malignancies are not well described. In this study, we presented a pedigree of RTS from a Chinese family, among which the proband was diagnosed with de novo myelodysplastic syndrome (MDS). Comprehensive medical examination and chromosome karyotyping were performed on the proband. Whole exome sequencing (WES) was performed on the proband, his sister and his mother. The familial cosegregation of sequence variants derived from WES was conducted by polymerase chain reaction-based Sanger sequencing. Structures of candidate RECQL4 mutants were done by in silico analysis to assess pathogenicity. Three novel germline variants, including c.T274C, c.G3014A, and c.G801C, were identified by WES and validated by Sanger sequencing. Prediction of conformation indicated that the structural stability of human RECQL4 protein was largely affected with these variants. The co-occurring p.S34F and p.Y220C mutations might contribute to the development of MDS. Our study expands the mutational spectrum of and provides underlying molecular mechanism for the development of MDS in RTS patients.
PubMed: 37228773
DOI: 10.1097/BS9.0000000000000152